Derivatives of 2-(4-aminophenylimino)-thiazolidine and 4h-5,6-dihydro-1,3-thiazines

ABSTRACT

2-(4-Aminophenylimino) derivatives of thiazolidine and -4H-5,6dihydro-1,3-thiazines, the corresponding amide and sulfonamide derivatives, and the salts thereof are anthelmintic agents. The compounds, of which 2-(4-aminophenylimino)-N-methylthiazolidine is a typical embodiment, are prepared through cyclization of a thiourea, optionally with subsequent hydrolysis, alkylation or acetylation.

United States Patent 1191 Wollweber et al.

[ Jan. 14, 1975 DERIVATIVES OF 2-(4-AMINOPHENYLIMINO)- THIAZOLIDINE AND4H-5,6-DIHYDRO-1,3-THIAZINES inventors: Hartmund Wollweber,

Wuppertal-Elberfeld, Germany; Winiried Flucke, Beenleigh, Queensland,Australia; Hans Peter Schulz; Herbert Thomas, both ofWuppertal-Elberfeld, Germany Bayer Aktiengesellschaft, Leverkusen,Germany Filed: Sept. 14, 1972 Appl. No.: 289,092

Assignee:

Foreign Application Priority Data Sept. 14, 1971 Germany 2145807 US. Cl260/243 R, 260/243 AE, 260/2565 R, 260/287 R, 260/3067 T,

Primary Examiner-Richard J. Gallagher [57] ABSTRACT2-(4-Aminophenylimino) derivatives of thiazolidine and-4H-5,6-dihydro-1,3-thiazines, the corresponding amide and sulfonamidederivatives, and the salts thereof are anthelmintic agents. Thecompounds, of which 2-(4-aminophenylimino)-N-methylthiazolidine is atypical embodiment, are prepared through cyclization of a thiourea,optionally with subsequent hydrolysis, alkylation or acetylation.

24 Claims, N0 Drawings DERIVATIVES F 2-(4-AMINOPHENYLIMINO)-THIAZOLIDINEAND 4H-5,6-DIHYDRO-1 ,3-THIAZINES thiacycloalkanes are known to possesspharmacodynamic activity such as for example anaesthetic, blood pressuredepressing and central nervous system action (see, eg H. Najcr et al.,Bull. 1961 960; and South African Patent 63/2420). The knownpharmacological activity of such compounds appears to be specificallyconnected with the o-substitution in the phenyl nucleous and none of thecompounds having such an arrangement possesses anthelmintic action.

The compounds of the present invention are characterized by the formula:

in which Z is an ethylene or trimethylene chain which is unsubstitutedor substituted by lower alkyl; R is lower alkyl, lower alkenyl or loweralkynyl;

The term lower alkynyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalacetylenic unsaturation as, for example, ethynyl, 2-propynyl,4-pentynyl, and the like.

The term cycloalkyl denotes a univalent saturated monocyclic hydrocarbonof from 3 to 7 carbon atoms as, for example, cyclopropyl, cyclobutyl,cyclopentyl,

cyclohexyl, and cycloheptyl.

The term lower alkoxy denotes a straight or branched hydrocarbon chainbound to the remainder of the molecule through an ethereal oxygen atomas, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy and hexoxy.

As indicated, the present invention also pertains to the physiologicallyacceptable non-toxic acid addition R is hydrogen, lower alkyl, loweralkenyl or lower alkynyl; and

each of R and R independent of the other, is hydrogen, lower alkyl,lower alkenyl, lower alkoxy, chloro, fluoro, bromo, nitro ortrifluoromethyl.

Also included within the scope of the present invention are the salts ofthe foregoing amines formed from pharmaceutically acceptable organic andinorganic acids and the amide and sulfonamide derivatives of thoseamines in which R is hydrogen.

The term alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from 1 to 18 carbon atoms. Representativeof such alkyl groups are thus methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, neopentyl,tert.pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,octadecyl, and the like. i

The term lower alkyl denotes aunivalent saturated branched or straighthydrocarbon chain containing from 1 to 6 carbon atoms. Representative ofsuch lower alkylgroups are thus methyl, ethyl, propyl, isopropyl,

butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl,

neopentyl, tert.pentyl, hexyl, and the like.

The term lower alkenyl denotesa univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalethylenic unsaturation as, for example, vinyl, allyl, isopropenyl,Z-butenyl, 3-methyl-2-butenyl, Z-pentenyl, 3-pentenyl, 2-hexenyl,4-hexenyl, and the like.

salts of these basic compounds. Such salts include those derived fromorganic and inorganic acids such as, without limitation, hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid. acetic acid, tartaric acid, lactic acid, succinic acid,citric acid, malic acid, maleic acid, sorbic acid, aconitic acid,salicylic acid, phthalic acid, embonic acid, enanthic acid, and thelike.

Preferred compounds are those wherein R is methyl, ethyl, allyl,methallyl or crotyl, R is methyl, ethyl, propyl, isopropyl or an amideor sulfamide residue, R is hydrogen and R is hydrogen or chloro.

The amide and sulfonamide embodiments of the present invention are thosederived from any of the well-known carboxylic and sulfonic acids,respectively. The structure of the residue of these acids does notappear to be critical and, as shown below, can vary widely withoutadversely affecting the activity of the parent amine moiety. Thus theseamides can be broadly described as those of Formula I wherein R is thegroup R CO-with R being hydrogen, lower alkyl, lower alkoxy, loweralkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, cycloalkyl,phenyl, phenoxy, or a heterocyclic group. The groups thus embraced by R,other than hydrogen, can in turn be further substituted. For example,the lower alkyl and lower alkoxy groups can be substituted by loweralkoxy, cycloalkyl, methyl substituted cycloalkyl, tetrahydrofuryl,thienyl, phenyl or phenoxy, with the phenyl or phenoxy substituents onsuch lower alkyl and lower alkoxy embodiments being in turn optionallysubstituted by chloro, fluoro, bromo, loweralkyl, lower alkoxy,trifluoromethyl or nitro. Similarly, when R is lower alkenyl or loweralkenyloxy, it can be substituted by phenyl which in turn can bear afurther substituent such as for example chloro. When R is cycloalkyl, itcan be substitutedby lower alkyl. When R is phenyl or phenoxy it cansimilarly be substituted as for example by chloro, fluoro, bromo, loweralkyl, lower alkoxy, nitro, trifluoromethyl, lower alkenoyloxy, loweralkanoyl or carbo (lower alkoxy). When R is a heterocyclic group, suchas furyl, thienyl, isoxazoyl, pyrimidinyl, imidazolyl, pyrazolyl,indolyl, thianaphthyl, quinolyl, phenothiazinyl, thiadiazolyl orthiazolyl, it can also be substituted, as for example by lower alkyl.Preferred amide derivatives are those wherein R is hydrogen, a loweralkyl, lower alkoxy or lower alkenyl group of up to 3 carbon atoms,lower alkynyloxy of up to 4 carbon atoms, cycloalkyl, fufuryl,S-methylisoxazolyl or phenyl. The sulfonamide derivatives can be broadlydescribed as a compound of Formula I wherein R is RSO with R being loweralkyl or phenyl, the phenyl group in turn being optionally substitutedby chloro, fiuoro, bromo, lower alkyl, lower alkoxy, trifluoromethyl ornitro. Preferred sulfonamides are those wherein R is methyl or ethyl.

In most instances, the preferred embodiments are generally those inwhich the lower alkyl and lower alkoxy groups present in the moleculecontain 1 to 3 carbon atoms and more specifically l or 2, the loweralkenyl, lower alkenyloxy lower alkynyl and lower alkynyloxy groupscontain 2 to 4 carbon atoms, and the cycloalkyl groups contain 5 or 6carbon atoms,

Typical compounds of the present invention include:2-(4-aminophenylimino)-N-methylthiazolidine;2-(4-aminophenylimino)-N-ethylthiazolidine;2-(4-amino-3-chlorophenylimino)-N- methylthiazolidine;2-(4-aminophenylimino)-N-methyl-4I-I-5,6-dihydrol,3-thiazine:2-(4-methylaminophenylimino)-N-methylthiazolidine;2-(4-allylaminophenylimino)-N-methylthiazolidine; and2-(4-isobutylaminophenylimino)-N- methylthiazolidine.

Typical of the amide derivatives of the present invention are:2-(4-carbethoxyaminophenylimino)-N- methylthiazolidine;2-(4-benzamidophenylimino)-N-methylthiazolidine;2-[4-(Z-furylcarbonyl)-aminophenylimino]-N- methylthiazolidine;2-(4acetamidophenylimino)-N-methylthiazolidine;2-(4-carbethoxyamino-3-chlorophenylimino)-N- methylthiazolidine;2(4-formamidophenylimino)-N-methylthiazolidine; 2-(4carbethoxyaminophenylimino)-N-methyl-4H-5,6- dihydro-l ,3-thiazine;2-[4-(4-chlorobenzamido)-phenylimino]-N- methylthiazolidine;2-[4-(3-chlorobenzamido)-phenylimino]-N- methylthiazolidine;2-[4-(2-chlorobenzamido)-phenylimino]-N- methylthiazolidine;2-[4-(4-methylbenzamido)-phenylimino]-N- methylthiazolidine;2-[4-(3-methylbenzamido)-phenylimino]-N- methylthiazolidine;2-[4-(Z-methylbenzamidol-phenyliminol-N- methylthiazolidine; and2-[4-(2.6-dichlorobenzamido)-phenylimino]-N- methylthiazolidine.

The compounds of the present invention are prepared utilizing a numberof synthetic procedures. Formation of the thiazolidine or4H-5,6-dihydro-l ,3- thiazine ring with simultaneous formation of theimino linkage is accomplished through cyclization of an appropriatethiourea of the formula:

4 in which R, R, R R and Z are as herein defined and X is chloro, bromo,hydroxy or sulfonyloxy. The same result can be obtained, possibly by insitu formation of a thiourea of Formula II, through use of a thiourea ofthe formula:

and a compound of the formula: IV

wherein R, R, R R Z and X are as herein defined and Y is as defined forX or amino,

The cyclization ofthe thioureas of Formula II and the reaction of thecompounds of Formulas Ill and IV can be carried out in a diluent or atmelt. The use of diluents is desirable but not absolutely essential, thechoice of the suitable diluent being determined by the stability andreactivity of the particular reactants. Any diluent which is inert tothe reaction can be employed, such as hydrocarbons, as for examplebenzene and ligroin, ethers such as diethyl ether and dioxan'e,halogenated hydrocarbons such as for example methylene chloride, esterssuch as ethyl acetate, alcohols such as methanol, ethanol and propanol,and water, as well as mixtures thereof, can be used. The cyclization ofthe thioureas is conducted in the presence of an aqueous or anhydrousstrong acids, as for example hydrochloric acid. hydrobromic acid,phosphoric acid, polyphosphoric acid, sulphuric acid, benzenesulphonicacid, methanesulphonic acid and the like. Reaction temperatures can bevaried over a wide range. In general the reaction is carried out atbetween 0 and C, conveniently at the boiling point of the diluent(although it is frequently advantageous to cool the reactants at thebeginning of the reaction).

The thioureas employed as starting materials are known or can be readilyobtained by known methods.

Thus for example, a phenylisothiocyanate and an amine are allowed toreact at a temperature of from about 10 to about 50C, in an inertsolvent such as ether or tetrahydrofuran. The amine component which isallowed to react with the thioisocyanate can be of the structureRHN-Z-X, yielding the thioureas of Formula II, or RH N, yielding thethioureas of Formula III. In

the former case, it is often advantageous to utilize an.

a l V R in which R, R R and Z are as herein defined. This compound,.uponreduction, yields the corresponding 4-amino compound, i.e., a compoundof Formula I wherein R is hydrogen.

This reduction can be carried out catalytically, as for example withhydrogen in the presence of a noble metal catalyst, optionally in thepresence of a diluent, such as an alcohol such as methanol or ethanol,ethanolic hydrochloric acid, or an ether such as tetrahydrofuran attemperatures of from 0 to 100C, preferably of 20 to 80C, optionallyunder pressure, for example at 1 to 100, preferably 60 to 80,atmospheres gauge.

The reduction can also be carried out chemically as withzinc/hydrochloric acid and tin-(ll) chloride, preferably in an aqueousmedium, with sodium sulphide in an alcohol or ether at a temperature of20 to 100C, preferably at the boiling point of the diluent, or with acomplex metal hydride such as sodium borohydrate at temperatures of from20 to 80C.

A preferred embodiment of the cyclization reactions for the compounds ofFormulas I1 and 111 are those in which RHN- is an amide function, e.g. RCOHN-. Upon completion of the cyclization, the amide group can behydrolyzed, again leading to the compounds of Formula 1 where R ishydrogen. This hydrolysis can be effected through the use of a strongacid, such as hydrochloric or sulfuric acid, in the presence of water ormixture of water and alcohol. This is generally performed at the boilingpoint of the aqueous acid mixture.

Compounds of Formula I wherein R is hydrogen which are thus obtained bythe above methods can in turn be alkylated (including alkenylation andalkynylation) or acylated to yield amides or sulfonated to yieldsulfonamides.

1n the case of alkylation, one can employ for example an alkyl, alkenylor alkynyl halide, such as the chloride, bromide or iodide, or thecorresponding arylsulfonyloxy or alkylsulfonyloxy derivatives such as abenzenesulfonyloxy or methanesulfonyloxy compound. One to two moles ofthe alkylating agent are employed, preferably in an inert organicsolvent such as diethyl ether, tetrahydrofuran or acetonitrile.Preferably an acid binding agent such as an alkali metal or alkalineearth metal carbonate or biscarbonate, or a tertiary amine, is present.The alkylation can be conducted at temperatures of from 20 to 80C.

Alkylation can also be accomplished through formation of a Schiff base,by the reaction of a compound of Formula I where R is hydrogen and anappropriate aldehyde or -ketone, followed by reduction of the Schifftetrahydrofuran, or aromatic hydrocarbons such as benzene and toluene.The Schiff bases thus obtained are hydrogenated, with or without priorisolation, either catalytically as with a noble metal catalyst orchemically. The catalytic reduction is preferably carried out at about20C and optionally under pressure of from 1 to atmoshperes gauge,preferably 60 atmospheres gauge with the same solvents described above.Chemical reduction can be carried out with complex metal hydrides suchas for example sodium borohydride, in which case approximately thestoichiometric amount of'metal hydride is employed. Here the reactioncan be carried outat temperatures of 20 to 80C.

The intermediate Schiff base can also be employed in a furtheralkylation. Thus treatment of a compound of Formula 1 wherein R ishydrogen with an aliphatic or aromatic aldehyde, quaternization of theresulting Schiff base with an alkyl, alkenyl or alkynyl halide, such asthe chloride, bromide or iodide, or the corresponding arylsulfonyloxy oralkylsulfonyloxy derivative, and hydrolytic cleavage of the aldehyderesidue yields the compounds of Formula I wherein R is alkyl, alkenyl oralkynyl. The Schiff base is formed in the same manner as describedabove. The quaternization is performed at temperatures of from about 20to about C, especially 60 to 80C, with or without isolation of theSchiff base. The hydrolysis is preferably executed, without isolation ofthe salt, by heating the salt in aqueous alcohol at temperatures of from20 to 100C, preferably 40 to 90C.

The amides andsulfonamides of the present invention are obtained fromcompounds of Formula 1 where R is hydrogen utilizing conventional andwell-known acylation and sulfonylation reagents, optionally with theconcurrent use of a solvent and/or acid binding agents. The reaction isconducted at temperatures of from 0 to C, generally 20 to 90C. Solventswhich can be employed are all organic solvents which are inert in thereaction, as for example aromatic hydrocarbons such as benzene ortoluene, petroleum ether, chlorinated hydrocarbons such as chloroform ormethylene chloride, tetramethylenesulphone, and the like. The acylationor sulphonylation agents include lower alkyl pyrocarbonic acid esters,chloroformic acid lower alkyl esters, lower alkylcarboxylic acidchlorides and bromides, formic acid alkyl esters, methanesulphonic acidchloride, aromatic and heterocyclic carboxylic acid chlorides andcarboxylic acid anhydrides. Preferably the lower alkyl groups of theseagents contain 1 to 4 carbon atoms.

It is also possible to perform the above described cyclizations ofthioureas in which R is hydrogen and to then alkylate the resultingN-unsubstituted thiazolidine or 4H-5,6-dihydro-l,3-thiazine. Thealkylation is performed at from about 0 to 120C, preferably 20 to 80C,using about stoichiometric amounts of a compound of the structure R-Bwhere R is as defined above and B is chloro, bromo, iodo,arylsulfonyloxy such as benzenesulfonyloxy, or lower alkylsulfonyloxysuch as methanesulfonyloxy. An inert organic solvent such as an ether orliquid lower alkyl nitrile is generally employed, e.g. diethyl ether,tetrahydrofuran, acetonitrile.

Utilization of the foregoing procedures, which are typified hereafter,thus permits formation of the compounds of the present invention.Although the individual species of these compounds can be genericallydepicted in a variety of formal groupings, and while each species isconsidered an equal embodiment of the iiivention, whether taken alone orin any combination with one or more species of the invention, thecompounds can in their broadest aspect be formally depicted by thestructural formula:

R1-HN wherein Z is ethylene or trimethylene which is:

(A) unsubstituted or (E.) substituted by lower alkyl; R is (A.) loweralkyl, (8.) lower alkenyl, or (C.) lower alkynyl; R is:

(A.) hydrogen, (8.) lower alkyl, (C.) lower alkenyl, (D.) lower alkynyl,(E.) the group RCO- in which R is (l) hydrogen (ll) lower alkyl or loweralkoxy which is:

(a.) unsubstituted or (b.) substituted by (1) lower alkoxy, (2)cycloalkyl which is (i) unsubstituted or (ii) substituted by methyl (3)tetrahydrofuryl, (4) thienyl. (5) phenyl or phenoxy which is (i)unsubstituted or (ii) substituted by [a] chloro. [b] fluoro,

[c] bromo, [d] lower alltyl, [e] lower alkoxy, [f] trifluoromethyl o [g]nitro;

(lll) lower alkenyl or lower alkenyloxy which is:

(a) unsubstituted or (b.) substituted by phenyl which is:

(l) unsubstituted or (Z) substituted by chloro; (lV) lower alkynyl orlower alkynyloxy;

(V) cycloalkyl which is:

('a.) unsubstituted or (b.) substituted by lower alkyl;

(Vl) phenyl or phenoxy which is:

(a.) unsubstituted or (b.) substituted by (l) ehloro, (2) fluoro, (3)bromo, (4) lower alkyl, (5) lower alkoxy, (6) nitro, (7)trifluoromethyl, (8) lower alkanoyloxy, (9) lower alkanoyl, or (10)carbo(lower alkoxy); or

(Vll) furyl, thienyl, isoxazolyl, pyrimidinyl.

imidazolyl. pyrazolyl, indolyl, thianaphthyl. quinolyl, phenothiazinylthiadiazolyl or thiazolyl which is:

(21,) unsubstituted or (b.) substituted by lower ulkyl; or

The compounds of this invention show very good activity againstnematodes, a substantially better effect than is demonstrated by otherknown anthelmintics, such as for example, bephenium hydroxynaphthoate,phenylene-l,4-diisothiocyanate, thiabendazole and piperazine.

In particular, the compounds show surprisingly good and broad actionagainst such nematodes as hookworms as for example, Ancylostoma caninum,Uncinaria stenocephala; Trichlostrongylids as for example, Haemonchuscontortus, Trichostrongylus colubriformis, Nippostrongylus muris, andNematospiroides dubius; Strongylids as for example, OesophagostomumColumbianum; threadworms as for example Srrongyloides ram; asearids asfor example, Toxocara canis, Toxascaris leonina and Ascaris suum;pinworms such as Aspiculuris telraptera; Heterakids as for example,Helerakis spumosa; and Filariae such as Litomosoides carinii andDipetalonema witei.

This action can be conveniently observed in animal models through oraland parenteral administration to test animals, severely infected withparasites, as seen from the following:

Hookworm Dogs experimentally infected with Ancylostoma caninum orUncinaria stenocephala were treated at the end of the prepatency of theparasites. The indicated amount of active compound was administeredorally as the pure active compound in gelatin capsules. The degree ofaction was determined by counting the worms expelled after thetreatment, and the worms remaining in the test animal after dissection,and calculating the percentage of worms expelled. The table whichfollows lists the active compounds, the type of parasite and the minimumdosage which reduces the worm infection of the test animals by more thanpercent (Red 90%), in comparison to commercially available preparations.

The dosage is quoted in mg of active substance per kg of body weight.

Compound Bephenium Parasite Table l-Continued Effective minimum dose(Red. 907.)

Anczlostoma caninum Uncinaria stenocephala in (mg/kg ThiabendazolePiperazine Ancxlostoma c ani num Uncinaria stenocephala Anczlostoma Onlypartial action Only partial action Only partial caninum action Lh'nmler,G. and E. Saupe (1969) Z. Trop. Parasitol. 2 0 346 Nematospiroidesdubius Mice experimentally infected with Nematospiroides 35 dubius weretreated after the end of the pre-patency period of the parasites. Theamount of active compound was administered orally as an aqueoussuspension.

The degree of action of the preparation is determined after dissection,in comparison to untreated control animals, and from this calculatingthe percentage action.

The table which follows lists the active compounds and the minimumdosage which reduces the infection of the test animals by worms by morethan 90 percent by counting the worms remaining in the test animal 40 incomparison to commercial Preparations- Compound Effective minimum dose(Red 907.) in mg/kg r1 21 0. N-C 1 Table 2 Continued Minimum effectivedose (Red. 907.)

Compound in trig/kg CH -C-NH- N o-ca -co-m n act" Thiabendazole 500Bephenium S00 the parasites. The amount of active compound was adEffective minimum ministered orally as an aqueous suspension. Compound'dose ff g The degree of action of the preparation was determined bycounting the worms remaining in the test aniigitoscarlate 2?) mal afterdissection, in comparison to untreated con- WA [Mum trol animals, andthereafter calculating the percentage action.

The table which follows lists the active compounds Strongyloides rattiand the minimum dosage which reduces the infection Rats experimentallyinfected with Strongyloides ratti by worms of the test animals by morethan 90 percent,

were treated after the end of the pre-patency period of 40 in comparisonto commercial preparations.

Table 3 Minimum effective dose Compound (Red )90"/,) in rug/kg I S fQ J2nc1 TABLE 3 (Iontinued C ompound Effective minimum dose (Red. 907)Parasite in rag/kg Y S l -Q n=c :l RC].

Thiabendazole Bephenium L000 Bitoscanate 2S0 Piperazine Inactive Ascaridtest tive compound was administered orally as an aqueous suspension.

The degree of action of the preparation is determined by counting theworms remaining in the test animal after dissection, in comparison tountreated control animals, and calculating the percentage actiontherefrom. 7

The table which follows lists the active compounds and the minimumdosage which reduces the infection of the test animals by worms by morethan percent, in comparison to commercial preparations.

Table 4 Minimum effective dose (Red. )907.) Compound Parasite in mgzkgAscaris suum (larvae) Ascaris suum 250 (larvae) Toxocara 25 CH canisTable 4v-Continued llinirium effective dose (Red. 901) CozzaoundParasite in nit/kg Ascaris suum 2 .5

(larvae) CH3 CH3 (larvae) Thiabendazole Ascaris suum I 500 (larvae)Tocascaris 5 x 50* leonina Ascaris suum Inactive Bitoscanate (larvae)Toxascaris 12 x 6** leonina Ascaris suum Inactive (larvae) PiperazineToxocara 200*** canis Toxascaris 200*** leonina l'lucke, w. (-1963) DieKleintierpraxis 176 Limler, G. and E. Slupe (1960) Z. Trap. Paruitol. Q,346

*** Xutzer, E. (1965) Wien. Tierirztl. Msehr. 5 2 242 Heterakis spumosaorally as an aqueous'suspension. r

Mice experimentally infected with Heterakis spumosa The degree ofaction-of the preparation is detc rmined were treated at the end of thepre-patency period of the 65 by counting the worms remaining in .thetest animal parasites. after dissection in comparison to untreatedcontrol ani- The amount of active compound was administered mals andcalculating the percentage action therefrom.

Table Minimum effective dose Compound (Red. 901) in trig/kg H N=c 2 H61I CH /S on -CO-NH-N- :1 100 Thiabendazole 500 Bitosc'anate Inactive Thecompounds of the present invention are administered parenterally ororally in any of the usual pharmaceutical forms. These include solid andliquid oral unit dosage forms such as tablets, capsules, powders,suspensions, solutions, syrups and the like, including sustained releasepreparations, and fluid injectable forms such as sterile solutions andsuspensions. The term unit dosage form as used in this specification andthe claims refer to physically discrete units to be administered insingle or multiple dosage to animals, each unit containing apredetermined quantity of active material in association with therequired diluent, carrier or vehicle. The quantity of active material isthat calculated to produce the desired therapeutic effect uponadministration of one or more of such units.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted diluent pharmaceutical carriersuch as an edible carbohydrate material as for example, starch.Sweetening, flavoring, preservative, dispersing and coloring agents canalso be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. A lubricant such as talc, magnesiumstearate and calcium stearate can be added to the powder mixture as anadjuvant before the filling operation; a glidant such as colloidalsilica may be added to improve flow properties; a disintegrating orsolubilizing agent may be added to improve the availability of themedicament when the capsule is ingested Tablets are made by preparing apowder mixture, granulating or slugging, adding a lubricant anddisintegrant and pressing into tablets. A powder mixture is prepared bymixing the compound, suitably comminuted, with a diluent or base such asstarch, sucrose, kaolin, dicalcium phosphate and the like. The powdermixture can be granulated by wetting with a binder such as syrup, starchpaste, acacia mucilage or solutions of cellulosic or polymeric materialsand forcing through a screen. As an alternative to granulating, thepowder mixture can be run through the tablet machine and the resultingimperfectly formed slugs broken into granules. The granules can belubricated to prevent sticking to the tablet forming dies by means ofthe addition of stearic acid, a stearate salt, talc or mineral oil. Thelubricated mixture is then compressed into tablets. The medicaments canalso be combined with free flowing inert carriers and compressed intotablets directly without going through the granulating or sluggingsteps. A protective coating consisting of a sealing coat of shellac, acoating of sugar or polymeric material and a polish coating of wax canbe provided. Dyestuffs can be added to these coatings to distinguishdifferent unit dosages.

Oral fluids such as syrups and elixirs can be prepared in unit dosageform so that a given quantity, e.g., a teaspoonful, contains apredetermined amount of the compound. Syrups can be prepared bydissolving the compound in a suitably flavored aqueous sucrose solutionwhile elixirs are prepared through the use of a nontoxic alcoholicvehicle. Suspensions can be formulated by dispersing the compound in anon-toxic vehicle in which it is insoluble.

Fluid unit dosage forms for parenteral administration can be prepared bysuspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively a measured amount of the compound is placed in-a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration. I

The compounds of the present invention are administered in doses of fromabout 1 mg/kg to about 100 mg/kg of body weight of the animal in need oftreatment, i.e., to an infected animal for therapeutic purprogress ofthe infection. In some cases it will suffice to use less than 1 mg/kgwhile in other cases more than 100 mg/kg must be administered. Wherelarger amounts are administered, it can be advisable to divide theseinto several individual administrations over the course of the day. Inall cases attention should be paid to the recognized and usualprecautions of medical and veterinary practice. i

The following examples will serve to further typify the nature of theinvention.

EXAMPLE 1 A mixture of 11.2 g of N-(4-carbethoxyaminophenyl)-N-methyl-N'-(B-hydroxyethyl)-thiourea and 35 mlof concentrated hydrochloric acid is heated at C for 30 minutes. Themixture is cooled and rendered alkaline with sodium hydroxide solution,and the oil which separates is taken up in chloroform. Afterevaporation, 9.8 g of 2-(4-carbethoxyaminophenylimino)-N-methylthiazolidine, melting point l27l28C,are obtained; the hydrochloride salt demonstrates a melting point of203205C. Yield: 94 percent of theory.

This compound can also be produced as follows: 29.7 g ofN-(4-carbethoxyaminophenyl)-N-methyl-N"-(B- hydroxyethyl)-thiourea aredissolved .in ml of methylene chloride. Twelve grams of thionyl chlorideare added dropwise and the mixture is then heated under reflux for 1hour. The mixture is evaporated in vacuo and crystallineN-(4-carbethoxyaminophenyl)- N'-methyl-N-(B-chloroethyl)-thiourea isobtained as the residue which is then heated with ml of water underreflux for 90 minute s. The mixture is cooled, rendered alkaline withsodium hydroxide solution and extracted with ether/chloroform. Afterevaporation of-the solvent and recrystallization from ethyl acetate,22.5 g of 2-(4-carbethoxyaminophenylimino)-N- methylthiazolidine areobtained. Yield: 81 percent of theory.

The starting material'can be prepared according to the followingprocedure:

7.5 g of N-methylethanolamine-are added to a solution of 22.2 g of4-carboethoxyaminophenylisothiocyanate in 200 ml of tetrahydrofuran at20 2 5C, with stirring. After concentration in a rotary evaporator andrecrystallization, N-(4-carboethoxyaminophenyl)-N-methyl-N-(,B-hydroxyethyl)-thiourea of melting point 131C is obtained.Alternatively, 7.5 g of N- methylethanolamine are added to 18 g of 4-nitrophenylisoeyanatc dissolved in 200 ml of tetrahydrofuran at 20 25C,with stirring. After mixing in a rotary evaporator,N-(4-Nitrophenyl)N-methyl-N'- (B-hydroxyethyl)thiourea is obtained,which is immediately processed further. 25.5 g of N-(4-nitrophenyl)-N'-methyl-N-(B-hydroxyethyl)thiourea are dissolved in 100 ml ofmethylene chloride and 12 g of thionyl -chloride are then added dropwiseand the mixture is heated for 1 hour under reflux and then evaporated invacuo. Crystalline N-(4-nitrophenyl)-N-methyl-N'-(B-chloroethyD-thiourea is obtained as the residue. This is heated withl25 ml of water for 90 minutes under reflux. The mixture is cooled,rendered alkaline with sodium hydroxide solution and extracted withether/chloroform. After evaporation and recrystallization from ethylacetate, 2-(4-nitrophenylimino)-N- methylthiazolidine is obtained. 7

The following compounds areprepared analogously from the appropriatethioureas:

2-(4-carbethoxyaminophenylimino)-N- ethylthiazolidine hydrochloride205206C with dec.;2-(4-carbethoxyaminophenylimino)-N-npropylthiazolidine;2-(4-carbethoxyaminophenylimino)-N- isopropylthiazolidine hydrochloride229231C with dec.; 2-(4-carbethoxyaminophenylimino)-N-n.butylthiazolidine hydrochloride 205206C with dec.;2-(4-carbethoxyaminophenylimino)-N- allylthiazolidine hydrochloride ofmp. 350C with dec.; 2-(4-carbethoxyaminophenylimino)-N-methallylthiazolidine;2-(4-carbethoxyaminophenylimino)-N-'ychloroallyl-thiazolidine;2-(4-carbethoxyaminophenylimino)-N-B- chloroallyl-thiazolidine;2-(4-carbethoxyaminophenylimino)-N-B-(ychloroally)-thiazlidine;2-(4-carbethoxyaminophenylimino)-N- crotylthiazolidine; and2-(4-carbethoxyaminophenylimino)-N- propargylthiazolidine.

EXAMPLE 2 A mixture of 2-(4-carbethoxyaminophenylimino)-N-methylthiazolidine and 150 ml of concentrated hydrochloric acid isheated under reflux for 16 hours. After evaporation of the solvent andrecrystallization of the residue from ethanol/water, 18.8 g of 2-(4-aminophenylimino)-N-methylthiazolidine hydrochloride, melting point270C, are obtained, from which the free base is obtained on addingsodium hydroxide solution, melting point 130 131C (recrystallized fromethyl acetate). Yield: 77.5 percent of theory.

of m.p.

of m.p.

of m.p.

EXAMPLE 3 Twelve grams of chloroformic acid ethyl ester are addeddropwise at 20C to a solution of 20.7 g of 2-(4-aminophenylimino)-N-methylthiazolidine in 150 ml of ethanol. The mixtureis heated at 60C for 1 hour and evaporated in vacuo. Afterrecrystallization from ethanol/ethyl acetate, 24.6 g of 2-(4-carbethoxyaminophenyl)-N-methylthiazolidine hydrochloride are obtained;melting point of fr ee bas TfF" 2-[4-carbo-(2-methoxyethoxy)-aminophenylimino]- N-methylthiazolidine;2-(4-carbocyclopropoxyaminophenylimino)-N- methylthiazolidine;2-(4-carbocyclobutoxyaminophenylimino )-N- methylthiazolidine;2-(4-carbocyclopentyloxyaminophenylimino )-N- methylthiazolidine;'2-(4-carbocyclohexyloxyaminophenylimino)-N- methylthiazolidine;2-(4-carbocyclohexylmethoxyaminophenylimino)- N-methylthiazolidine;2-(4-carbobenzoxyaminophenylimino)-N- methylthiazolidine;2-[4-carbo-(2-phenethoxy)-aminophenylimino]-N- methylthiazolidine;2-(4-carbotetrahydrofuryloxyaminophenylimino )-N- methylthiazolidine;2-(4-carbofurfuryloxyaminophenylimino)-N- methylthiazolidine;2-(4-carbothienyl-( 2 )-methoxy-aminophenylimino]- N-methylthiazolidine;2-(4-carbophenoxyaminophenylimino )-N- methylthiazolidine; and2-[4-carbo-(4-ch1orophenoxy)-aminophenylimino]- N-methylthiazolidine.

EXAMPLE 4 Using the method described in Example 3, 20.7 g of2-(4-aminophenylimino)-N-methylthiazolidine, dissolved in ml of ethanol,and 16.9 g of benzoyl chloride yield 28.5 g of2-(4-benzoylaminophenylimino-N- methylthiazolidine hydrochloride,metling point 279C (with decomposition). The free base is obtained byadding sodium hydroxide solution, crude melting point 172C,naphthalenedisulphonate melting point 296C(with decomposition), (82percent of theory). Using the appropriate acid chlorides, the followingare obtained by proceeding analogously:

2-[4-(4-chlorobenzoylamino)-phenylimino]-N- methylthiazolidinehydrochloride of melting point 300C;2-[4-(3-chlorobenzoylamino)-phcnylimino]-N- methylthiazolidinehydrochloride of melting point 279 281C (with dec.);2-[4-(2-chlorobenzoylamino)-phenylimino]-N- methylthiazolidinehydrochloride of melting point 279 281C (with dec.);2-[4-(4-methylbenzoylamino)-phenylimino]-N- methylthiazolidinehydrochloride of melting point 281 283C (with dec.);2-[4-(3-methylbenzoylamino)-phenylimino]-N- methylthiazolidinehydrochloride of melting point 267C (with dec.);2-[4-(2-methylbenzoylamino)-phenylimino]-N- methylthiazolidinehydrochloride of melting point 279 281C (with dec.);2-[4-(2,6-dichloroben2oylamino)-phenylimino]-N- methylthiazolidinehydrochloride of melting point 300C;2-[4-(4-nitrobenzoylamino)-phenylimino]-N- methylthiazolidinehydrochloride of melting point 310C (with dec.); 2-[4-(3-nitrobenzoylamino)-phenylimino]-N- methylthiazolidine hydrochloride ofmelting point 301 302C (with dec.);

27 methylthiazolidine hydrochloride (85 percent of theory) of meltingpoint 146 150C (with dec.). The free base is obtained therefrom onaddition of sodium hydroxide solution.

The following are obtained by proceeding analogously:

2-[4-(5-methylisoxazolyl-3-carbonylamino)-phenylamino]-N-methylthiazolidine;2-[4-(Z-pyridylcarbonylamino)-phenylimino]-N- methylthiazolidine;2-[4-(3-pyridylcarbonylamino)-phenylimino]-N- methylthiazolidine;2-[4-(4-pyridylcarbonylamino)-phenylimino]-N- methylthiazolidine;2-[4-(Z-furfurylcarbonylamino)-phenylamino]-N- methyl-thiazolindine;2-[4-(Z-indolylcarbonylamino)-phenylimino]-N- methyl-thiazolidine;2-[4-(Z-thianaphthylcarbonylamino)-phenylimino]- N-methylthiazolidine;2-[4-( 3-indolylacetylamino)-phenylimino]-N- methylthiazolidine;2-[4-(3-quinolylcarbonylamino)-phenylimino]-N- methylthiazolidine;2-[4-( 2-phenothiazinylcarbonylamino)-phenylimino]-N-methylthiazolidine; thienylacetylamino)-phenylimino]-N-methylthiazolidine; 2-[4-(3-pyrazo1ylcarbonylamino)-phenylimino]-N-methylthiazolidine; 2-[4-(4-methyl-3-pyrazoly1carbonylamino)-phenylimino]-N-methylthiazo1idine;2-{4(Z-imidazolylcarbonylamino)-phenylimino]-N- methylthiazolidine;2-[4-(2-pyrazinylcarbonylamino)-phenylimino]-N- methyl-thiazolidine;2-[4-(4-pyrimidinylcarbonylamino)-phenylimino]- N-methylthiazolidine;2-[4-(S-thiazolylcarbonylamino)-phenylimino]-N- methylthiazolidine; and2-[4-(Z-thienylcarbonylamino)-phenylimino]-N- methylthiazolidine.

EXAMPLE 6 Following the procedure described in Example 3, 103 g of2-(4-aminophenylimino)-N- methylthiazolidine and 9 g of acetyl chlorideyield 13.3

of 2-(4-acetylaminophenylimino)-N- methylthiazolidine hydrochloride,free base melting point 170 173C. Yield: 94 percent of theory.

The following are similarly obtained:

2-(4-propionylaminophenylimino)-N- methylthiazolidine;2-(4-butyrylaminophenylimino)-N- methylthiazolidine;2-(4-isobutyrylaminophenylimino)-N- methylthiazolidine;2-(4-pivaloylaminophenylimino)-N- methylthiazolidine;2-(4-valeroylaminophenylimino)-N- methylthiazolidine;2-(4-acryloy1aminophenylimino)-N- methylthiazolidine;2-(4-crotonoylaminophenylimino)-N- methylthiazolidine;2-(4-methacryloylaminophenylimino)-N- methylthiazolidine;

28 propinylcarbonylaminophenylimino)-N- methylthiazolidine;

2-(4-methoxyacetylaminophenylimino)-N- methylthiazolidine, mp 197 198C;2-(4-cyclopropylcarbonylaminophenylimino)-N- methylthiazolidine;2-(4-cyclobutylcarbonylaminophenylimino)-N- methylthiazolidine;2-(4-cyclopentylcarbonylaminophenylimino)-N- methylthiazolidine; 2-(4-cyclohexylcarbonylaminophenylimino)-N- methylthiazoline;2-(4-cycloheptylcarbonylaminophenylimino)-N- methylthiazolidine;2-[4-(3-methylcyclopentylcarbonylamino)-phenylimino]-N-methylthiazolidine;2-[4-(4-methylcyclohexylcarbonylamino)-phenylimino]-N-methylthiazolidine;2-(4-cyclopent-2-enylcarbonylamino)-phenylimino)- N-methylthiazolidine;and 2-(4-cyclohex-1-enylcarbon ylaminophenylimino)-N-methylthiazolidine.

Analogously, the use of alkanesulphonic acid chlorides instead of acetylchloride according to Example 6 yields:

2-(4-methylsulphonylaminophenylimino)-N- methylthiazolidinehydrochloride of melting point 260 262C (with dec.);2(4-ethylsulphonylaminophenylimino)-N- methylthiazolidine hydrochloride;2-(4-butylsulphonylaminophenylimino)-N- methylthiazolidinehydrochloride; 2-(4-isobutylsulphonylaminophenylimino)-N-methylthiazolidine hydrochloride;2-(4-hexylsulphonylaminophenylimino)-N- methylthiazolidinehydrochloride; 2-(4-allylsulphonylaminophenylimino)-N-methylthiazolidine hydrochloride;2-(4-methallylsulphonylaminophenylimino)-N- methylthiazolidinehydrochloride; 2-(4-crotonylsulphonylaminophenylimino)-N-methylthiazolidine hydrochloride;2-(4-cyclopropylsulphonylaminophenylimino)-N- methylthiazolidinehydrochloride; 2-(4-cyc1opentylsuIphonylaminophenylimino)-N-methylthiazolidine hydrochloride;2(4-cyclohexylsulphonylaminophenylimino)-N- methylthiazolidinehydrochloride; 2-(4-cycloheptylsulphonylaminophenylimino)-N-methylthiazolidine hydrochloride;2-(4-dodecylsulphonylaminophenylimino)-N- methylthiazolidinehydrochloride; 2-(4-propylsulphonylaminophenylimino)-N-methylthiazolidine hydrochloride; and2-(4-isopropylsulphonylaminophenylimino)-N- methylthiazolidinehydrochloride.

EXAMPLE 7 By substituting the appropriate amount of N-(3-chloro-4-carbethoxyaminophenyl )-N '-methyl-N '-(B-hydroxyethyl)-thiourea in the procedure of Example 1, there is obtained2-( 3-chloro-4- carbethoxyaminophenylimino)-N-methylthiazolidinehydrochloride, mp. 194C (dec.). This compound, when subjected to theprocedure of Example 2, yields 2-(3-chloro-4aminophenylimino)-N-methylthiazolidine, mp 104. C.

Similarly obtained are:

2-(2,5-dichloro-4 carbethoxyaminophenylimino)-N- methylthiazolidinehydrochloride;

2-(3-methyl-4-carbethoxyaminophenylimino)-N- methylthiazolidinehydrochloride; 2-(2-methyl-4-carbethoxyaminophenylimino)-N-methylthiazolidine hydrochloride;2(2,6-dimethyl-4-carbethoxyaminophenylimino)-N- methylthiazolidinehydrochloride; 2-(3-allyl-4-carbethoxyaminophenylimino)-N-methylthiazolidine hydrochloride;

2-( 3-fluoro-4-carbethoxyaminophenylimino)-N- methylthiazolidinehydrochloride;

2 (2-chloro-4-acetylaminophenylimino)-N- methylthiazolidinehydrochloride;

2-(3-chloro-4-benzoylaminophenylimino)-N- methylthiazolidinehydrochloride;

2-(3-trifluoromethyl-4- methacryloylaminophenylimino)-N-methylthiazolidine hydrochloride; 7

2-( 3 -bromo-4-4-carbisopropoxyaminophenylimino N-methylthiazolidinehydrochloride;

2(3methoxy-4-carbethoxyaminophenylimino)-N- methylthiazolidinehydrochloride;

2 (3-cyano-4-carbethoxyaminophenylimino)-N- methylthiazolidinehydrochloride;

2-(2-trifluoromethyl-4- carbethoxyaminophenylimino)-N-methylthiazolidine hydrochloride;

2-( 3-trifluoromethyl-4- carbethoxyaminophenylimino)-N-methylthiazolidine hydrochloride; and

2-( 3 -bromo-4-carbethoxyaminophenylimino )-N- methylthiazolidinehydrochloride. 7

EXAMPLE 8 By sequentially following the procedure of Examples 1 and 2,there is ultimately obtained from the corresponding N'-allylthiourea,the compound 2-(4- aminophenylimino)-N-allylthiazolidine which, as thedihydrochloride, melts at 245C.

EXAMPLE 9 7.8 g of formic acid-acetic anhydride are added dropwise at20C to 10.3 g of 2(4-aminophenylimino)-N- methylthiazolidine and themixture is heated at 50 to 60C for 1 hour. Eighty milliliters of icewater are added and the mixture is evaporated in vacuo. The residue isrendered alkaline with sodium hydroxide solution and extracted withchloroform. After evaporation and distillation (boiling point 178182C/O.2 mm), 7.9 g of 2-(4-formylaminophenylimino)-N-methylthiazolidine (67 percent of theory), are obtained.

EXAMPLE 10 Following the procedure described in Example 1, 31.1 g ofN-(4-carboethoxyaminophenyl)-N-methyl- N'-('y-hydroxypropyl)-thiourea,melting point 142 143C, and 100 ml of concentrated hydrochloric acid areallowed to react to yield 16.6 g of 2-(4-carbethoxyphenylimino)-N-methyl-4H-5,6-dihydro- 1,3-thiazine, meltingpoint 178 180C in a yield of 57 percent of theory.

EXAMPLE 11 To 18 g of 4-nitrophenylisocyanate in 200 ml oftetrahydrofuran are added with stirring at 20 to C, 7.5

g of N-methylethanolamine. The product, N-(4-nitrophenyl)-N-methy1-N-(2-hydroxyethyl)-thiourea, is obtained on arotary evaporator and used immediately in the following procedure. To asolution of 25.5 g of this thiourea in ml of methylene chloride areadded dropwise 12 g of thionyl chloride. The mixture is heated at refluxfor 1 hour. Evaporation in vacuo yields N-(4-nitrophenyl)-N'-methyl'N'-(2-chloroethyl) thiourea. This is heated under refluxwith ml of water for 90 minutes. After cooling, the solution is renderedalkaline with sodium hydroxide and extracted with ether/chloroform.Evaporation and recrystallization of the residue from ethyl acetateyields 2-(4- nitrophenylimino)-N-methylthiazolidine, m.p. 95 96C.

A solution of 23.7 g of 2-(4-nitrophenylimino)-N- methylthiazolidine in400 ml of acetic acid is hydrogenated in the presence of platinum oxideat 20C until 0.3 mole of hydrogen is taken up. The catalyst is removedby filtration and the solution is evaporated in vacuo. The residue istaken up in water, sodium hydroxide solution is added and the base whichseparates out is extracted with a solution of ether and chloroform.After evaporation of the organic layer, 16.5 g of pure2-(4-aminophenylimino)-N-methylthiazolidine, melting point 127 128C, areobtained in a yield of 80 percent of theory.

EXAMPLE 12 Ten grams of isobutyraldehyde are added dropwise to 20.7 g of2-(4-aminophenylimino)-N- methylthiazolidine, dissolved in 300 ml ofbenzene, at 20C, the mixture is heated for 2 hours under a waterseparator and 2-(4-isobutylideneaminophenylimino)- N-methylthiazolidineis distilled in vacuo, boiling point 175 178C/0.3 mm. Nine grams ofdimethyl sulphate are then added to a solution of 14 g of this compoundin ml of benzene. The mixture is heated for 1 hour under reflux and thebenzene is decanted. The residue is taken up in 30 ml of 50 percentstrength ethanol and this solution is heated for 1 hour under reflux.After evaporation in vacuo and adding sodium hydroxide solution to theresidue, the free base is extracted with ether and distilled, boilingpoint 162 l65C/0.2 mm. The following compounds are obtained analogously:2(4-ethylaminophenylimino)-N-methylthiazolidine;2-(4-propylaminophenylimino)-N- methylthiazolidine;2-(4-butylaminophenylimino)-N-methylthiazolidine;2-(4-isobutylaminophenylimino)-N- methylthiazolidine;2-(4-allylaminophenylimino)-N-methylthiazolidine;2-(4-propargylaminophenylimino)-N- methylthiazolidine; 2-(4-crotylaminophenylimino)-N-methylthiazolidine;

and 2-(4-isopropylaminophenylimino)-N- methylthiazolidine.

EXAMPLE l3 1 Twenty grams of the 2-(4-isobutylideneaminophenylimino)-N-methylthiazolidine obtained accordingto Example 12, dissolved in 250 ml of tetrahydrofuran, are hydrogenatedwith palladiumon-carbon catalyst at 20C. After filtering off thecatalyst Y and distilling, 13.5 g of -2-(4-isobutylaminophenylimino)-N-methylthiazolidine,

boiling point 170 l73C/O.22 mm are obtained in a yield of 67 percent oftheory.

EXAMPLE 14 Methyl iodine (15.8 g) is added dropwise to a solution of26.5 g of 2-(4-carbethoxyaminophenylimino)- thiazolidine (m.p. 146147C), in 250 ml of tetrahydrofuran, at 20C. The mixture is heated for 4hours under reflux and then evaporated in vacuo. The residue is taken upin a mixture of chloroform/ether and this solution is extractedrepeatedly with water. The organic phase is evaporated and afterrecrystallization from ethyl acetate, 8.5 g of 2-(4-carbethoxyaminophenylimino)-N-methylthiazolidinc, m.p. l27 128C, areobtained in a yield of 30 percent of theory.

EXAMPLE l Fifteen grams of N-(4-carbethoxyaminophenyl)-N-methyl-thiourea are heated with 100 ml of 1,2- dibromoethane for hoursunder reflux. After cooling, the crystals are removed by filtration anddissolved in water. The solution is rendered alkaline and 2-(4-carboethoxyaminophenylimino)-N-methylthiazolidine is isolated in thefashion described in Example 1, mp. 127 128C.

What is claimed is:

1. A compound of the formula:

1 s\ R-NH 2 or a pharmaceutically.acceptable salt thereof, wherein Z isethylene or trimethylene unsubstituted or substituted by lower alkyl;

R is lower alkyl, lower alkenyl or lower alkynyl;

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, R CO or RSOwherein R is (a) hydrogen, (b) lower alkyl or lower alkoxy which isunsubstituted or substituted by l lower alkoxy; (2) cycloalkyl of 3to 7carbon atoms which is unsubstituted or substituted by methyl; (3)tetrahydrofuryl; (4) thienyl or (5) phenyl or phenoxy which isunsubstituted or substituted by chloro, fluoro, bromo, lower alkyl,lower alkoxy, trifluoromethyl or nitro; (c) lower alkenyl or loweralkenyloxy which is unsubstituted or substituted by chloro; (d) loweralkynyl or lower alkynyloxy; (e) cycloalkyl of 3to 7 carbon atoms whichis unsubstituted or substituted by lower alkyl; (f) phenyl or phenoxywhich is unsubstituted or substituted by chloro, fluoro, bromo, loweralkyl, lower alkoxy, nitro, trifluoromethyl, lower alkanoyloxy, loweralkanoyl or carbo(lower alkoxy); or (g) unsubstituted or lower alkylsubstituted furyl, thienyl, isoxazolyl, pyrimidinyl, imidazolyl,pyrazolyl, indolyl, thianaphthyl, quinolyl, phenothiazinyl, thiadiazolylor thiazolyl and R is (a) lower alkyl which is unsubstituted orsubstituted by (l) cycloalkyl of 3 to 7 carbon atoms which isunsubstituted or substituted by methyl, or (2) phenyl which isunsubstituted or substituted by chloro,

fluoro, bromo, lower alkyl, lower alkoxy, trifluoromethyl or nitro, or(b) lower alkenyl; and

each of R and R independent of the other, is hydrogen, lower alkyl,lower alkenyl, lower alkoxy, chloro, nitro, or trifluoromethyl.

2. A compound according to claim 1, wherein R is R CO wherein R is (a)hydrogen, (b) lower alkyl or lower alkoxy which is unsubstituted orsubstituted by (1) loweralkoxy; (2) cycloalkyl of 3 to 7 carbon atomswhich is unsubstituted orsubstituted by methyl; (3) tetrahydrofuryl; (4)thienyl or (5) phenyl or phenoxy which isunsubstituted or substituted bychloro, fluoro, bromo, lower alkyl, lower alkoxy, trifluoromethyl ornitro; (c) lower alkenyl or lower alkenyloxy which is unsubsti tuted orsubstituted by chloro; (d) lower alkynyl or lower alkynyloxy; (e)cycloalkyl of 3 to 7 carbon atoms which is unsubstituted or substitutedby lower alkyl; (f) phenyl or phenoxy which is unsubstituted orsubstituted by chloro, fluoro, bromo, lower alkyl, lower alkoxy, nitro,trifluoromethyl, lower alkanoyloxy, lower alkanoyl or carbo(loweralkoxy); or (g) unsubstituted or lower alkyl substituted furyl, thienyl,isoxazolyl, pyrimidinyl, imidazolyl, pyrazolyl, indolyl, thianaphthyl,quinolyl, phenothiazinyl, thiadiazolyl or thiazolyl.

3. A compound according to claim 2 wherein Z is ethylene ortrimethylene;

R is methyl, ethyl, allyl, methallyl or crotyl;

R is hydrogen;

R is hydrogen or chloro; and

R is hydrogen, lower alkyl of up to 3 carbon atoms,

lower alkenyl of 3 carbon atoms, lower alkoxy of up to 3 carbon atoms,lower alkynyloxy of up to 4 carbon atoms, cycloalkyl of 3 to 5 carbonatoms, phenyl, furyl or S-methylisoxazolyl.

4. A compound according to claim 1, wherein R is R 50 wherein R is (a)lower alkyl which is unsubstituted or s ub st it ut ed by (l) cycloalkylof 3 to 7 carbon atoms which is unsubstituted or' substituted by methyl,or (2) phenyl which is unsubstituted or substituted by chloro, fluoro,bromo, lower alkyl, lower alkoxy, trifluoromethyl or nitro, or (b) loweralkenyl.

5. A compound according to claim 4 wherein Z is ethylene ortrimethylene,

R is methyl, ethyl, allyl, methallyl or crotyl;

R is hydrogen;

R is hydrogen or chloro; and

R is lower alkyl.

6. A compound according to claim 1 wherein R is hydrogen, lower alkyl,lower alkenyl or lower alkynyl.

7. A compound according to claim 6 wherein Z is ethylene ortrimethylene;

R is methyl, ethyl, allyl, methallyl, or crotyl;

R is methyl, ethyl, propyl, isopropyl or allyl;

R is hydrogen; and

R is hydrogen or chloro.

8. The compound according to claim 1 which is 2-(4-carbethoxyaminophenylimino)-N-methylthiazolidine.

9. The compound according to claim 1 which is 2-(4-aminophenylimino)-N-methylthiazolidone.

10. The compound according to claim 1 which is 2-(4-benzamidophenylimino)-N-methylthiazolidine.

H. The compound according to claim I which is 2-[4-(2-l'urylcarbonyl)-nminopheuyliminol-N- mcthylthiazolidinc.

[4-(3-chlorobenzamido)-phenylimino]-N- methylthiazolidine 20. Thecompound according to claim 1 which is 2-[4-(2-chlorobenzamido)-phenylimino]-N- methylthiazolidine.

21. The compound according to claim 1 which is 2-[4-(4-methylbenzamido)-phenylimino]-N- methylthiazolidine.

22. The compound according to claim 1 which is 2-[4-(3-methylbenzamido)-phenylimino]-N- methylthiazolidine.

23. The compound according to claim 1 which is 2- [4-( 2-methylbenzamido)-phenylimino]-N- methylthiazolidine.

24. The compound according to claim 1 which is 2-[4-(2,6-dichlorobenzamido)-phenylimino]-N- methylthiazolidine.

2. A compound according to claim 1, wherein R1 is R6CO wherein R6 is (a)hydrogen, (b) lower alkyl or lower alkoxy which is unsubstituted orsubstituted by (1) lower alkoxy; (2) cycloalkyl of 3 to 7 carbon atomswhich is unsubstituted or substituted by methyl; (3) tetrahydrofuryl;(4) thienyl or (5) phenyl or phenoxy which is unsubstituted orsubstituted by chloro, fluoro, bromo, lower alkyl, lower alkoxy,trifluoromethyl or nitro; (c) lower alkenyl or lower alkenyloxy which isunsubstituted or substituted by chloro; (d) lower alkynyl or loweralkynyloxy; (e) cycloalkyl of 3 to 7 carbon atoms which is unsubstitutedor substituted by lower alkyl; (f) phenyl or phenoxy which isunsubstituted or substituted by chloro, fluoro, bromo, lower alkyl,lower alkoxy, nitro, trifluoromethyl, lower alkanoyloxy, lower alkanoylor carbo(lower alkoxy); or (g) unsubstituted or lower alkyl substitutedfuryl, thienyl, isoxazolyl, pyrimidinyl, imidazolyl, pyrazolyl, indolyl,thianaphthyl, quinolyl, phenothiazinyl, thiadiazolyl or thiazolyl.
 3. Acompound according to claim 2 wherein Z is ethylene or trimethylene; Ris methyl, ethyl, allyl, methallyl or crotyl; R2 is hydrogen; R3 ishydrogen or chloro; and R6 is hydrogen, lower alkyl of up to 3 carbonatoms, lower alkenyl of 3 carbon atoms, lower alkoxy of up to 3 carbonatoms, lower alkynyloxy of up to 4 carbon atoms, cycloalkyl of 3 to 5carbon atoms, phenyl, furyl or 5-methylisoxazolyl.
 4. A compoundaccording to claim 1, wherein R1 is R7SO2 wherein R7 is (a) lower alkylwhich is unsubstituted or substituted by (1) cycloalkyl of 3to 7 carbonatoms which is unsubstituted or substituted by methyl, or (2) phenylwhich is unsubstituted or substituted by chloro, fluoro, bromo, loweralkyl, lower alkoxy, trifluoromethyl or nitro, or (b) lower alkenyl. 5.A compound according to claim 4 wherein Z is ethylene or trimethylene, Ris methyl, ethyl, allyl, methallyl or crotyl; R2 is hydrogen; R3 ishydrogen or chloro; and R7 is lower alkyl.
 6. A compound according toclaim 1 wherein R1 is hydrogen, lower alkyl, lower alkenyl or loweralkynyl.
 7. A compound according to claim 6 wherein Z is ethylene ortrimethylene; R is methyl, ethyl, allyl, methallyl, or crotyl; R1 ismeThyl, ethyl, propyl, isopropyl or allyl; R2 is hydrogen; and R3 ishydrogen or chloro.
 8. The compound according to claim 1 which is2-(4-carbethoxyaminophenylimino)-N-methylthiazolidine.
 9. The compoundaccording to claim 1 which is2-(4-aminophenylimino)-N-methylthiazolidone.
 10. The compound accordingto claim 1 which is 2-(4-benzamidophenylimino)-N-methylthiazolidine. 11.The compound according to claim 1 which is2-(4-(2-furylcarbonyl)-aminophenylimino)-N-methylthiazolidine.
 12. Thecompound according to claim 1 which is2-(4-acetamidophenylimino)-N-methylthiazolidine.
 13. The compoundaccording to claim 1 which is2-(4-carbethoxyamino-3-chlorophenylimino)-N-methylthiazolidine.
 14. Thecompound according to claim 1 which is2-(4-amino-3-chlorophenylimino)-N-methylthiazolidine.
 15. The compoundaccording to claim 1 which is2-(4-formamidophenylimino)-N-methylthiazolidine.
 16. The compoundaccording to claim 1 which is2-(4-carbethoxyaminophenylimino)-N-methyl-4H-5,6-dihydro-1,3-thiazine.17. The compound according to claim 1 which is2-(4-isobutylaminophenylimino)-N-methylthiazolidine.
 18. The compoundaccording to claim 1 which is2-(4-(4-chlorobenzamido)-phenylimino)-N-methylthiazolidine.
 19. Thecompound according to claim 1 which is2-(4-(3-chlorobenzamido)-phenylimino)-N-methylthiazolidine.
 20. Thecompound according to claim 1 which is2-(4-(2-chlorobenzamido)-phenylimino)-N-methylthiazolidine.
 21. Thecompound according to claim 1 which is2-(4-(4-methylbenzamido)-phenylimino)-N-methylthiazolidine.
 22. Thecompound according to claim 1 which is2-(4-(3-methylbenzamido)-phenylimino)-N-methylthiazolidine.
 23. Thecompound according to claim 1 which is2-(4-(2-methylbenzamido)-phenylimino)-N-methylthiazolidine.
 24. Thecompound according to claim 1 which is2-(4-(2,6-dichlorobenzamido)-phenylimino)-N-methylthiazolidine.